Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2−/− mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2−/− lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2−/− and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2−/− fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2−/− mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF

Analysis of Serum Fatty Acids and Vitamin D with Dimension Reduction Methods

Fatty acid plays an important role in human health and fat-related diseases. A comprehensive analysis of diverse fatty acids in serum naturally results in a multi-variable, high-dimensional dataset, and, therefore, multivariate analysis, especially dimension reduction, should be considered to extract useful information. In this study, three basic dimension reduction methods including factor analysis, principal component analysis, and independent component analysis were conducted on total and free fatty acid datasets in a general Japanese population (N=545; men:women=245:300). These analyses successfully characterized fatty acid datasets, reflecting their physicochemical natures, metabolisms, and food sources. Factor analysis and principal component demonstrated the association of -3 fatty acids (20:5 and 22:6) with 25-hydroxyvitamin D3 (vitamin D), suggesting fish oil as their common source of vitamin D. We conclude that dimension reductions can serve as a useful tool to extract valuable information from complex datasets of fatty acids and vitamin D in the aspect of health care and disease control

Light Higgsino in Heavy Gravitino Scenario with Successful Electroweak Symmetry Breaking

We consider, in the context of the minimal supersymmetric standard model, the case where the gravitino weighs 10^6 GeV or more, which is preferred by various cosmological difficulties associated with unstable gravitinos. Despite the large Higgs mixing parameter B together with the little hierarchy to other soft supersymmetry breaking masses, a light higgsino with an electroweak scale mass leads to successful electroweak symmetry breaking, at the price of fine-tuning the higgsino mixing mu parameter. Furthermore the light higgsinos produced at the decays of gravitinos can constitute the dark matter of the universe. The heavy squark mass spectrum of O(10^4) GeV can increase the Higgs boson mass to about 125 GeV or higher.Comment: 13 pages, 3 figures; v2: version to appear in JHE

Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys

ヒト・サルの胎児卵巣から原始卵胞を体外で作出することに成功. 京都大学プレスリリース. 2022-08-01.New egg recipe to boost fertility research. 京都大学プレスリリース. 2022-08-14.In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates

Commuting quantum transfer matrix approach to intrinsic Fermion system: Correlation length of a spinless Fermion model

The quantum transfer matrix (QTM) approach to integrable lattice Fermion systems is presented. As a simple case we treat the spinless Fermion model with repulsive interaction in critical regime. We derive a set of non-linear integral equations which characterize the free energy and the correlation length of $$ for arbitrary particle density at any finite temperatures. The correlation length is determined by solving the integral equations numerically. Especially in low temperature limit this result agrees with the prediction from conformal field theory (CFT) with high accuracy.Comment: 17 page

RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL